Advanced Quantitative Magnetization Transfer Imaging in Multiple Sclerosis Disease Multiple sclerosis (MS) is a complex neurodegenerative disease that is highly variable in symptoms, clinical course, and underlying pathological changes in neural tissues. While magnetic resonance imaging (MRI) has become an important diagnostic tool providing noninvasive evidence of MS lesions, conventional MRI correlates poorly with clinical disability and its prognostic value is very limited. Specific and more sensitive imaging biomarkers are needed immediately to monitor disease progression, provide early outcome measures in clinical trials, and guide clinical decisions regarding current treatment options, particularly during the early stages of the disease. These biomarkers are also necessary to measure the effectiveness of emerging approaches to neuroprotection and myelin repair, such as stem cell transplantation. Ultimately, developing these biomarkers will allow identification of patients who are most likely to benefit from early treatment with disease-modifying therapy. Magnetization transfer imaging (MTI) probes can reveal otherwise occult treatment effects on demyelination and axonal loss by creating sensitivity to immobile bound protons immeasurable by conventional MRI. MT contrast is sensitive to subtle changes in macromolecular tissue composition, not only within but also beyond lesions visible in conventional MRI, and shows promise for prediction of disability and detection of MS pathology before it becomes visible on conventional MRI scans. However, MR system-dependent factors and the multi-parametric nature of MRI create confounding factors that limit the specificity and accuracy of MTI and thus restrict its clinical utility as a biomarker in assessing MS. Truly quantitative MTI (qMTI) methods can circumvent these crippling deficiencies if rapid calibration and measurement of other MR parameters can be obtained in a reasonable scan time. In addition, quantitative imaging requires repetitive sampling along a parametric dimension, creating a clinically impractical method that requires a several-fold increase in scan time. The overarching aim of this proposal is to generate truly quantitative biomarkers with improved specificity through the development of clinically feasible, quantitative MRI methods based on magnetization transfer. We have noticed that redundant information in the parametric sampling dimension can be exploited through new image estimation reconstruction methods to dramatically accelerate imaging methods. Specifically, our first aim will develop quantitative MRI methods that provide inherent calibration. The aim centers on developing robust 3D radial imaging methods compatible with parallel imaging capabilities. The variable sampling density with these trajectories allows acceleration through undersampling, but more importantly provides a foundation for accelerating qMTI through model-based image reconstruction algorithms developed in the second aim. Finally, the third aim will measure the ability of qMT biomarkers to predict clinical disability and lesion evolution and enable early detection of pathology in a small population of MS patients and age-matched controls. The project will leverage several unique resources and capabilities in a broad MS research program at UW- Madison. If successful, the techniques will not only change care and treatment development in MS, but will also be useful for the study, diagnosis, and clinical management of other white matter-based diseases including neurodegenerative, neoplastic, developmental and psychiatric disorders. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is the single most common debilitating neurological disease afflicting young adults in the U.S. It is incurable and it strikes during the prime years of adult life (patients are typically diagnosed in their 20's, 30's or 40's), resulting in a staggering loss of quality of life and a total economic cost to the U.S. of $6.8 billion annually (1998 estimate). The development of therapies for MS is greatly impeded by the lack of noninvasive measures of the disease course, which can progress substantially before objective signs or symptoms become apparent to the patient or his physician. This critical need for noninvasive measures of the disease can be met through advances in MRI technology; the overarching aim of this research is to identify sensitive and specific MRI markers for MS disease that will guide the application of current therapies and foster the development of promising new therapeutic approaches such as stem cell transplantation.